Le travail de cette thèse s’inscrit dans le cadre du projet ANR SUSoSTRESS qui a pour objectif la compréhension des mécanismes moléculaireset génétiques sous-jacents à la variabilité individuelle de réponses de stress et a collecté des données longitudinales à plusieurs niveaux biologiquessur une population d’étude porcine (race Large White). La thèse est organisé en deux partie. La première partie s’articule autour de l’analyse de données cliniques et transcriptomiques collectées à plusieurs pas de temps avant et après application de deux types de stress : injection d’ACTH et de LPS. Dans cettepartie, on cherche à développer d’un modèle fonctionnel permettant de décrire et d’intégrer au mieux l’ensemble des sources de variation génétique du fonctionnement de l’axe corticotrope et plus généralement des réponses de stress dans notre population d’étude. Plus précisément, il s’agit d’élaborer un modèle (au sens biologique du terme) décrivant les différentes réponses biologiques de stress et l’influence des variations génétiques (simples et en interaction), dans le but de prédire les leviers les plus efficaces en fonction de l’objectif de sélection. Ce travail a mis en évidence une liste de 65 gènes différentiellement exprimé au cours des réponses au stress, dont un ensemble de 8 gènes liés au au cortisol (l’hormone principale du stress) par NR3C1, le récepteur aux glucocorticoides. Ces gènes sont des biomarqueurs potentiels pouvant être fournis aux éleveurs en tant que leviers de sélection permettant un meilleur équilibre entre amélioration des caractères de production et des caractères de robustesse. La deuxième partie de ce travail s’articule autour du développement d’un outil d’analyse statistiques adapté à l’intégration de données ’omiques longitudinalesavec une variable cible d’intérêt.Nous proposons la «multiway-SIR », qui étend la méthode dual-STATIS, une méthode d’analyse de données cubiques non supervisée, au cadre de la SIR, une méthode de régression semi-paramétrique pouvant être utilisée à des fins exploratoires. Cette méthode est appliquée sur les données cliniques de l’expérience d’ACTHet permet d’y explorer l’influence de la variabilité de la réponse du cortisol à une injection d’ACTH. / This PhD thesis is part of the SUSoSTRESS project. This ANR funded project aims at improving the knowledge about molecular and genetic mechanisms underlying inter-individual variability in stress responses. Longitudinal data were collected at several biological levels on a porcine population (Large White). This work is structured in 2 parts. The first part is built around clinical and transcriptomic longitudinal data analyses collected before and after 2 types of stress factors : ACTH and LPS injection. The aim of this contribution is to develop a functional model describing all sources of genetic variation in the HPA axis activity and in stress responses in our study population.More precisely, it aims at defining a model describing the different biological stress responses and the influence of genetic variations in order to identify the most efficient selection levers according to selection goals. This work allowed for the identification of 65 differentially expressed genes during stress responses. Among them, 8 genes were highly linked to cortisol (the main stress hormone) through NR3C1 (glucocorticoid receptor (GR)). These genes are potential biomarkers and can be communicated to breeders as selection levers for a better trade-off between production and robustness traits in farmanimals. The second part is built around the development of a statistical tool suited for the data integration of repeated omicmeasurements with a real target variable.We introduce the "multiway-SIR" approach which extends the dual-STATIS (an approach to study 3-way datasets) method to the SIR framework (a semi-parametric regression model that can be used in an exploratory way). This method is illustrated on clinical data from the ACTH experiment. It allows for the exploration of the link between clinical variable response over time and inter-individual variability in the cortisol response to an ACTH injection.

BACKGROUND: Obesity is a leading health burden of the 21st century. Alterations of the individual endocrine stress response and the monoamine system may pathophysiologically contribute to the obesity pandemic and its metabolic and mental complications. OBJECTIVES: (i) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its relation to serum concentrations of the arginine-vasopressin (AVP) surrogate copeptin in subjects with obesity (OB) compared to non-obesity controls (NOC), (ii) to test whether HPA axis responsiveness and copeptin are related to central noradrenaline (NA) transporter (NAT) availability, (iii) to assess brain serotonin transporter (SERT) binding potentials in OB compared to NOC. METHODS: 40 subjects with obesity (BMI > 35kg/m2) were compared to 25 non-obesity controls, matched for age and sex. (i) All individuals underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters were derived, and copeptin was assessed in the 1500h sample. (ii) Positron emission tomography (PET) was applied in 10 OB and 10 NOC using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and associated to curve indicators derived from the dex/CRH test as well as to copeptin. (iii) PET using the SERT selective radiotracer [11C] DASB was performed in 30 OB and 15 NOC for intergroup comparison. RESULTS: (i) OB subjects showed an increased HPA axis responsiveness as measured by cortisol concentrations after CRH stimulation. Correspondingly, the AVP surrogate copeptin was higher in OB along with being significantly associated to HPA axis reactivity. OB subjects had a higher adrenal sensitivity as measured by a lower ACTH/cortisol ratio. (ii) In NOC, the HPA response was related to NAT availability of the amygdala and the orbitofrontal cortex while in OB, this association was located in the hypothalamus. (iii) There were no differences in SERT availability between OB and NOC, but a higher inter-regional SERT connectivity was observed in OB. CONCLUSION: This work supports the notion of an increased endocrine stress response in human obesity, pointing to interacting alterations of the HPA and neurohypophyseal axes. Normally, these stress axes seem to be linked to prefrontal-limbic NA signaling, whereas a loss of this association in favor of a hypothalamic-centered relation is observed in OB. The SERT network pattern is more closely inter-related in OB, albeit central SERT concentrations per se do not differ between OB and NOC.:ABBREVIATIONS 4 LIST OF FIGURES 5 I. BIBLIOGRAPHIC DESCRIPTION 6 II. INTRODUCTION 7 2.1 Obesity as a global health burden 7 2.2 Neurobiology of stress 8 2.3 Stress and obesity 8 2.4 Neuroendocrine correlates of the stress response – The hypothalamic pituitary-adrenaland neurohypophyseal axes 9 2.4.1 Anatomy of the hypothalamic-pituitary-adrenal and neurohypophyseal axes 10 2.4.2 The role of CRH, ACTH and cortisol in the context of metabolism and obesity 11 2.4.3 The role of AVP in the context of metabolism and obesity 12 2.4.4 Measuring HPA axis responsiveness by means of the combined dexamethasonecorticotropin-releasing hormone (dex/CRH) test 12 2.4.5 Measuring AVP secretion by its equally-released surrogate copeptin 14 2.5 The noradrenergic system in the context of obesity and stress axis modulation 14 2.5.1 NA and its influence on feeding behavior16 2.5.2 The association of the noradrenergic system with the HPA and neurohypophyseal axes 16 2.5.3 Monoamine transporters as regulators of neurotransmitter signaling 17 2.5.4 Noradrenaline transporter imaging 18 2.6 The serotonergic system in obesity 19 2.6.1 Role of serotonin in the context of feeding behavior and metabolism 20 2.6.3 5-HTT imaging 21 2.7 Objectives and hypotheses 22 2.8 Study design 23 III. RESULTS 24 3. 1 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity 24 3. 2 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls 34 3. 3 Central serotonin transporter availability in highly obese individuals compared with nonobese controls: A [11C] DASB positron emission tomography study 46 IV. SUMMARY 56 4.1 Subjects with obesity show an enhanced HPA axis responsiveness which correlates to serum concentrations of the AVP surrogate copeptin and abdominal fat distribution 56 4.2 HPA axis responsiveness and copeptin concentrations are differentially related to central NAT availability in subjects with obesity compared to non-obesity controls 58 4.3 Central serotonin transporter availability does not significantly differ in subjects with obesity compared to their non-obesity counterparts 59 4.4 Future direction 61 V. References 62 VI. APPENDICES 79 6.1 Curriculum vitae 79 6.2 Publications 81 6.3 Scientific contribution of the doctoral candidate to the publications 82 6.4 Declaration of the independent writing of this thesis 83 6.5 Acknowledgements 84

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that may develop in response to traumatic or stressful events. Dysfunction of the Hypothalamic-Pituitary-Adrenal (HPA) axis has been implicated in the disorder. Studies support such dysfunction as being a consequence of PTSD, rather than a precursor. However, most studies of the HPA are either cross-sectional or have been carried out in adults. The aim of the present study was to identify whether HPA dysregulation interacts with stressful experiences to increase the likelihood of developing PTSD symptoms in a community-recruited sample of healthy adolescent girls. Adolescent girls (N = 550) and one of their parents participated. Adolescents’ clinical symptoms were assessed at baseline and at a nine month follow-up. Saliva samples were collected from all adolescent participants at waking, 30 minutes after waking, and 8 pm on 3 consecutive days. Flattened diurnal slope of cortisol at baseline was associated with increased PTSD symptoms nine months later. Baseline cortisol awakening response (CAR) per se was not prospectively related to developing PTSD symptoms, but its interactions with stressful experience was associated with elevated PTSD symptoms at follow-up. Effects were small and need to be replicated in samples with more severe stressors, as well as more clinical levels of PTSD. Nevertheless, findings suggest that dysregulated basal HPA functioning may be involved in the development of PTSD symptoms.

BACKGROUND: The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood and exerts anti-inflammatory and neuroprotective effects. Its projections reach hypothalamic nuclei which regulate the neuroendocrine stress response. Changes in noradrenergic signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. Associated studies of our study group—investigating stress response in obese and non-obese subjects—have shown increased activity of the stress axes including an association between hypothalamic-pituitary-adrenal (HPA) axis responsiveness and central noradrenaline transporter. OBJECTIVES: (i) To evaluate central NA transporter (NAT) availability in vivo in immunotherapy-naïve relapsing-remitting multiple sclerosis (RRMS) patients compared to healthy controls (HC), (ii) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and the arginine-vasopressin surrogate (AVP) copeptin in patients with RRMS and clinically isolated syndrome (CIS) compared to HC, (iii) to test whether HPA axis responsiveness is differentially associated to NAT availability in RRMS patients and HC. METHODS: 22 patients (11 RRMS, 11 CIS) were enrolled and compared to 22 sex- and age-matched HC. (i) Positron emission tomography (PET) was performed in 11 RRMS and 12 HC applying the NAT-selective radiotracer S,S-[11C]O-methylreboxetine ([11C]MRB) for intergroup comparison. (ii) All patients underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters, and copeptin after dexamethasone intake were derived. (iii) MRB-PET imaging data were correlated to curve indicators and copeptin obtained from the dex/CRH test in RRMS patients. RESULTS: (i) RRMS patients show increased NAT availability in almost all subcortical regions, reaching statistical significance in the thalamus, amygdala, putamen and pons/midbrain. No association with clinical or psychometric variables was found. (ii) Immunotherapy-naïve RRMS patients show no significant changes in cortisol, ACTH or copeptin indices. (iii) There is no correlation between HPA axis indicators and NAT availability in RRMS patients. In HC, NAT availability correlated positively with cortisol curve indicators. CONCLUSION: This study supports the evidence for increased NAT availability in immunotherapy-naïve RRMS patients compared to HC. The increased NAT availability was shown in the subcortical brain regions (relevant to attention and emotional regulation) of the RRMS patients. In this cohort, no correlation with physical or psychometric scores was found. It will be further of interest, if these NAT changes longitudinally predispose to the psychiatric comorbidities which are frequently seen in MS patients or if they do in larger, more heterogenous sample sizes. Our cohort of early RRMS and CIS did not display a statistically significant alteration in the HPA axis responsiveness compared to HC. No association between NAT availability and HPA axis responsiveness could be detected in RRMS patients.:TABLE OF CONTENTS LIST OF ABBREVIATIONS…………………….………………………………………......4 LIST OF FIGURES…..….………………………….….……..…………………………..…5 I BIBLIOGRAPHIC DESCRIPTION…………………………..……………………………6 II INTRODUCTION…..…..………………………………………………………….............7 2.1 Multiple sclerosis — Background and scope……………....…………………..........7 2.1.1 Diagnostic criteria, subtypes and clinical features……….............….…………....7 2.1.2 Multiple sclerosis and its impact on daily life: fatigue.…...…...….............………9 2.2. Noradrenaline — neurotransmitter and immunomodulator…...…………….........10 2.2.1 Noradrenaline in the context of multiple sclerosis…………………….................11 2.2.2 Noradrenaline in the context of neuroinflammation and neurogenesis.............12 2.3 Noradrenaline transporter as regulator of noradrenergic transmission….…........13 2.3.1 Noradrenaline transporter imaging……………………………............................14 2.4 Neuroendocrine stress response……...…..……………………..……..……….......14 2.4.1 Noradrenaline in the context of stress response regulation…...........................15 2.4.2 Stress axis regulation in multiple sclerosis……….............……….....................16 III METHODS……………......……………………………………………………..……....19 3.1 Objectives and hypotheses.....……..…………………………………………….......19 3.2 Study design………………..….....………………………………….…..…………….20 3.3 Hypothalamic-pituitary-adrenal axis assessment using the combined dexamethasone/CRH test…….……...........……….....................................................21 3.4 Questionnaires……...…………………….....…………………………………………22 3.4.1 Beck-Depression-Inventory……………….............……….………………………22 3.4.2 Würzburger Erschöpfungsinventar bei MS….…………..….............……………22 3.5 PET imaging, imaging data processing and analysis………………….....………..23 3.6 Statistical analysis………………….………………………………………….....……23 IV RESULTS………….......……………………………………………….........................24 4.1 Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients – Publication….....……...…………24 4.2 HPA axis responsiveness does not differ between HC and RRMS or CIS patients…...………………………………...……………………………………….25 4.3 In RRMS patients, noradrenaline transporter availability of selected brain regions does not correlate with neuroendocrine indicators of stress responsiveness, but do positively correlate in healthy controls………………..….…..25 V SUMMARY………………….…………………………………………………………….31 5.1 Significantly changed noradrenaline transporter availability in RRMS patients in brain regions relevant to attention, vigilance and mood………….............31 5.2 Noradrenaline transporter availability is not significantly associated with psychometric and physical scores……..…………………...........................................32 5.3 HPA responsiveness does not significantly differ between early-stage RRMS patients, CIS patients and healthy controls………..…………………..............32 5.4 NAT DVR of selected brain regions do not reveal a significant association to HPA response in RRMS patients, but in healthy controls………...……..................33 5.5 Limitations..………………………………………………………………………….....35 5.6 Future directions…………………………………………………………………….....35 VI PUBLICATION BIBLIOGRAPHY…….……………………....…………….................36 VII ANHANG…….………..…...…..………..………………………………………………49 7.1 Publikationen…………..……….....…..……………………………………................49 7.1.1 Publikationen als Ko-Autorin…...…………..………..............…………………….50 7.1.1.1 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls……..50 7.1.1.2 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity...............................................................................51 7.2 Erklärung zum wissenschaftlichen Beitrag der Promovendin zur Publikationspromotion…………...........………………………………………………52 7.3 Erklärung über die eigenständige Abfassung der Arbeit...…....…………...…......53

There is now considerable evidence that both schizophrenia and affective disorders have their origin at least in part in events that occur during early pre- and post-natal development. In the case of schizophrenia, many observations, for example, increased risk for schizophrenia in the offspring of mothers who had influenza A during their second trimester of pregnancy and evidence for abnormal neuronal migration in the cerebral cortex of post mortem tissue from schizophrenic patients, suggest that a second trimester insult may have occurred and that this insult may have increased the risk for the development of schizophrenia in late adolescence or early adulthood. Animal studies have found that rats that undergo excitotxic damage to the ventral hippocampus on postnatal day 7 develop exaggerated sensitivity to dopamine-stimulating drugs or to stressful stimuli that becomes apparent after sexual maturity but not before, providing a neurodevelopmental model of schizophrenia. Similarly, post-weaning social isolation leads to nehanced responses to dopaminergic drgus and to stress that emerges after sexual maturity. These animal models are proving to be valuable tools to study the neurobiological mechanisms mediating the influence of early insults to the nervous system on later behavioural functins. In the case of affective disorders, although the evidence is not as strong, a number of the same observations have been made suggesting that an insult during early ontogeny may lead to the development of affective disorders later in life. For example, retrospective studies of people with affective disorders showed that they were more likely to have attained motor milestones at a later age and to have had poorer academic performance as children. There is a wealth of evidence suggesting hyperfunctioning of the hypothalamic-pituitary-adrenal (HPA) axis in affective disorders. Animal studies have shown that early matenal deprivation can lead to lasting changes in the reactivity of the HPA axis to stressful stimuli, providing another link from early experience to adult psychopathology. Continued studies of the effects of pre- and early post-natal events on the development of the nervous system and the relationships of these events to schizophrenia or affective disorder will provide new insights into the mechanisms underlying these common neuropsychiatric illnesses.

No description available.

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Thesis (MSc (Physiological Sciences))--University of Stellenbosch, 2006. / Early adverse life events appear to increase the susceptibility of developing psychiatric disorders later in life. The molecular mechanisms involved in the development of pathological behaviour remain unclear. Dysregulation of the hypothalamic-pituitary-adrenal axis and alterations in neurotrophic factors have been implicated.

Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. Acute ethanol activates the hypothalamic pituitary adrenal (HPA) axis causing the release of adrenal glucocorticoid hormones, but following chronic ethanol the HPA axis is dysregulated in both humans and rodents. Thus, there is growing evidence that glucocorticoids might also modulate behavioral and molecular responses to ethanol. Previous microarray studies in the Miles’ laboratory have shown that the well-known glucocorticoid responsive gene, Serum and Glucocorticoid-regulated Kinase 1, Sgk1, is prominently up regulated by acute ethanol (2 g/kg) in the prefrontal cortex (PFC) of DBA/2J mice. Functionally, Sgk1 is an important focal point of intracellular signaling cross-talk through which the cell surface receptors, nuclear receptors, and cellular stress pathways converge to control many cellular processes including receptor or ion channel trafficking, cell proliferation and/or apoptotic responses. In the aforementioned microarray studies, Sgk1 was accompanied by a highly correlated group of genes, many of which are also known to respond to glucocorticoids. This suggests that stress-related signaling events might play an important role in ethanol regulation of the Sgk1 gene network. Prior work by others showed that Sgk1 plays an important role modulating synaptic plasticity occurring in memory. Based on these findings, it is hypothesized that glucocorticoids and glucocorticoid responsive genes are responsible for modulating acute and chronic cellular and behavioral responses to ethanol including locomotor activation and ethanol sensitization. In particular, because Sgk1 is regulated by ethanol, has a well-established role in learning and memory and is responsive to glucocorticoid signaling we hypothesize that Sgk1 is involved in modulating acute and chronic cellular and behavioral responses to ethanol including ethanol sensitization. Our results indicate that the induction of glucocorticoid responsive genes may play a role in regulating acute behavioral and cellular responses to ethanol. Adrenalectomized (ADX) and mifepristone (RU-486) both impaired acute ethanol (2 g/kg) induced locomotor activation in DBA/2J mice without affecting basal locomotor activity. ADX mice showed microarray gene expression changes in the PFC that significantly overlapped with acute ethanol-responsive gene sets derived by our prior microarray studies. Additionally, acute ethanol regulates Sgk1 transcription via glucocorticoid receptor binding to the Sgk1 promoter. Furthermore, increases in Sgk1 may occur to compensate for decreases in SGK1 protein and phosphorylation of SGK1 and its well-known target N-myc downstream-regulated gene 1 (NDRG1) is significantly increased 15 minutes following ethanol administration. Finally, Sgk1 intensifies and prolongs the expression phase of sensitization in D2 mice. Our studies suggest that ethanol’s activation of adrenal glucocorticoid release and subsequent glucocorticoid receptor activation may partially modulate ethanol’s acute locomotor activation in male D2 mice. Furthermore, adrenal glucocorticoid basal tone regulates PFC gene expression. A significant set of acute ethanol-responsive genes are regulated by adrenal glucocorticoid basal tone suggesting that glucocorticoid regulated PFC gene expression may be an important factor modulating acute behavioral responses to ethanol. Sgk1 is acutely regulated following ethanol administration by the glucocorticoid receptor binding to the Sgk1 promoter. Altogether, these results suggest a critical role for the hypothalamic pituitary adrenal axis and Sgk1 in regulating the acute and chronic cellular and behavioral responses to ethanol.

Ecstasy é o nome popular do 3,4-metilenodioximetanfetamina (MDMA), uma droga de abuso utilizada por adultos jovens. Diversos relatos têm mostrado existência de correlações positivas entre o abuso do Ecstasy e o aparecimento de doenças infecciosas. Muitos estudos em modelos animais mostram que o MDMA induz alterações de imunidade inata e adquirida; entretanto pouco se sabe sobre os mecanismos pelos quais estes efeitos ocorrem. Desta forma, buscamos neste trabalho os mecanismos neuroimunes pelos quais o MDMA diminui a atividade de neutrófilos e altera a distribuição de leucócitos nos diferentes compartimentos imunes. Além disso, avaliamos se os efeitos induzidos pelo MDMA afetam a resposta a uma infecção experimental induzida por Listeria monocytogenes. Nossos resultados mostram que 60 minutos após a administração de MDMA na dose 10mg/kg, houve 1) diminuição do burst oxidativo de neutrófilos induzido por SAPI e PMA e, também, da porcentagem e da intensidade da fagocitose dos neutrófilos sanguíneos; 2) diminuição da celularidade total da medula óssea e aumento da mesma no baço, além de diminuição do peso relativo do baço; 3) aumento na porcentagem de neutrófilos e diminuição na porcentagem de linfócitos sanguíneos; e 4) diminuição da expressão de NFB de neutrófilos sanguíneos. O tratamento com metirapona ou RU-486 prévio ao tratamento com MDMA foi capaz de inibir 5) os efeitos observados em todos os parâmetros avaliados na diminuição da atividade de neutrófilos; 6) as alterações das porcentagens de neutrófilos e linfócitos sanguíneos e 7) a diminuição da expressão de NFB. Observamos, ainda, que o tratamento com 6-OHDA ou ICI-118,551 prévio ao tratamento com MDMA 8) não foram capazes de inibir os efeitos induzidos pelo MDMA na atividade de neutrófilos e na contagem diferencial de leucócitos sanguíneos; no entanto, 9) preveniram as alterações de celularidade induzidas por MDMA na medula óssea e no baço, e 10) a diminuição do peso relativo do baço. Por fim, observamos em um modelo de infecção experimental por LM que o MDMA 11) induziu mielosupressão (diminuição do CFU na medula óssea e aumento no baço); 12) diminuiu o número de leucócitos sanguíneos e a celularidade da medula óssea; 13) aumentou a celularidade do baço; 14) diminuiu a produção de citocinas pró-inflamatórias (IL-12p70, TNF, IFN-, IL-6) e quimiocina (MCP-1) nas primeiras 24 h; e 15) aumentou a produção das mesmas citocinas e quimiocina após 72 h da indução da infecção. Desta forma, concluímos que os efeitos induzidos pelo MDMA sobre a atividade de neutrófilos foram provavelmente mediados pela diminuição da expressão de NFB induzido pela ação da corticosterona e que a corticosterona, também está envolvida com as alterações na contagem diferencial de neutrófilos e linfócitos. As catecolaminas periféricas responderam pelas alterações na distribuição de leucócitos entre baço e medula óssea, e diminuição do peso relativo do baço. Além disso, o MDMA pode ser considerado uma droga imunossupressora visto que diminuiu a resistência a uma infecção por LM por mecanismos neuroimunes / Ecstasy is the popular name of 3,4-metylendioxymetamphetamine (MDMA), a drug of abuse mainly used by young adults. Several reports have shown the existence of a positive correlation between Ecstasy abuse and increased susceptibility to infectious diseases. Some studies using animal models report that MDMA induces alterations in both innate and adaptive immunity, however little is known about the mechanisms that generate such alterations. Therefore, we sought for neuroimmune mechanisms that could be involved in the previously reported decreasing on neutrophil activity and alteration in the leukocyte distribution. Moreover, we analyzed the host resistance to Listeria monocytogenes after MDMA treatment. We show that MDMA (10 mg/kg), 60 min after administration: 1) decreases SAPI and PMA-induced oxidative burst and percentage/intensity of phagocytosis of circulating neutrophils; 2) decreases bone marrow cellularity while increases it in the spleen, and also decreases spleen relative weight; 3) increases neutrophil percentage while decreases lymphocyte percentage in the blood; and 4) decreases NFB expression on circulating neutrophils. Metyrapone or RU-486 prior to MDMA treatment abrogates 5) the MDMA effects previously reported on neutrophil activity; 6) alterations in the percentage of circulating neutrophils and lymphocytes, and 7) decreasing of NFB expression. We also show that 6-OHDA or ICI-118,551 prior to MDMA treatment were not able to 8) abrogated the MDMA effects previously reported on neutrophil activity and blood leukocyte differential counts; nevertheless, 9) they abrogated the previously reported alterations on bone marrow and spleen cellularity, and 10) reduction on spleen relative weight. Finally, in a model of host resistance to Listeria monocytogenes we show that MDMA: 11) induces myelosuppression by decreasing CFU on bone marrow while increasing it on spleen; 12) decreases circulating leukocytes and bone marrow cellularity; 13) increases spleen cellularity; 14) decreases pro-inflammatory cytokines production (IL-12p70, TNF, IFN-, IL-6) and chemokine (MCP-1) after 24h of the infection; and 15) increases the production of the pro-inflammatory cytokines and chemokines previously reported after 72h of the infection. Thus, we conclude that the MDMA effects on neutrophil activity were mediated by the reduction of NFB expression, and this effect was induced by corticosterone elevation in the serum. Corticosterone is also involved in the alterations on neutrophil and lymphocyte counts. Catecholamines were shown to be involved in the alterations on leukocyte distribution in the bone marrow and spleen, and in the reduction of relative weight of spleen. Additionally, MDMA reduced the host resistance to Listeria monocytogenes. Therefore, MDMA can be considered an immunosuppressive drug and those effects are mediated by neuroimmune mechanisms